Interaction of the renin inhibitor aliskiren with the SARS-CoV-2 main protease: a molecular docking study

The renin protein is an upstream enzymatic regulator of the renin-aldosterone-angiotensin system (RAAS) essential for the maintenance of blood pressure. The angiotensin-converting enzyme-2 (ACE2) is a major component of the RAAS and a cell surface receptor exploited by the SARS-CoV-2 virus to enter host cells. A recent molecular modeling study has revealed that the direct renin peptide inhibitor remikiren can bind to the catalytic site of SARS-CoV-2 main protease (M^pro). By analogy, we postulated that the non-peptidic drug aliskiren, a more potent renin inhibitor than remikiren and a drug routinely used to treat hypertension, may also be able to interact with M^pro. An in silico comparison of the binding of the two compounds to M^pro indicates that aliskiren (ΔE = -75.9 kcal/mol) can form stable complexes with the main viral protease, binding to the active site, as remikiren (ΔE = -83.2 kcal/mol). The comparison with a panoply of 30 references compounds (mainly antiviral drugs) indicated that remikiren is a potent M^pro binder comparable to drugs like glecaprevir and pibrentasvir (ΔE = -96.5 kcal/mol). The energy of interaction (ΔE) of aliskiren with M^pro is about 10% lower than with remikiren, comparable to that calculated with drugs like velpatasvir and sofosbuvir. A model is proposed to define the drug binding site, with the best binders (including remikiren) penetrating deeply into the site, whereas the less potent binders (including aliskiren) interact more superficially with the protein.Communicated by Ramaswamy H. Sarma.